title: A key role for EZH2 in epigenetic silencing of HOX genes in mantle cell lymphoma.
abstract: The chromatin modifier EZH2 is overexpressed and associated with inferior outcome in mantle cell lymphoma (MCL). Recently, we demonstrated preferential DNA methylation of HOX genes in MCL compared with chronic lymphocytic leukemia (CLL), despite these genes not being expressed in either entity. Since EZH2 has been shown to regulate HOX gene expression, to gain further insight into its possible role in differential silencing of HOX genes in MCL vs. CLL, we performed detailed epigenetic characterization using representative cell lines and primary samples. We observed significant overexpression of EZH2 in MCL vs. CLL. Chromatin immune precipitation (ChIP) assays revealed that EZH2 catalyzed repressive H3 lysine 27 trimethylation (H3K27me3), which was sufficient to silence HOX genes in CLL, whereas in MCL H3K27me3 is accompanied by DNA methylation for a more stable repression. More importantly, hypermethylation of the HOX genes in MCL resulted from EZH2 overexpression and subsequent recruitment of the DNA methylation machinery onto HOX gene promoters. The importance of EZH2 upregulation in this process was further underscored by siRNA transfection and EZH2 inhibitor experiments. Altogether, these observations implicate EZH2 in the long-term silencing of HOX genes in MCL, and allude to its potential as a therapeutic target with clinical impact.
authors.affiliation: Department of Clinical Chemistry and Transfusion Medicine; Institute of Biomedicine; Gothenburg University; Gothenburg, Sweden.
authors.forename: Meena
authors.initials: M
authors.lastname: Kanduri
authors.affiliation: Department of Laboratory Medicine; Division of Pathology; Karolinska Institutet and Karolinska University Hospital; Huddinge, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Sander
authors.affiliation: Hematology Department and HCT Unit G. Papanicolaou Hospital; Thessaloniki, Greece; Institute of Applied Biosciences; CERTH; Thessaloniki, Greece.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Ntoufa
authors.affiliation: Hematology Department and HCT Unit G. Papanicolaou Hospital; Thessaloniki, Greece; Institute of Applied Biosciences; CERTH; Thessaloniki, Greece.
authors.forename: Nikos
authors.initials: N
authors.lastname: Papakonstantinou
authors.affiliation: Department of Immunology, Genetics and Pathology; Uppsala University; Uppsala, Sweden.
authors.forename: Lesley-Ann
authors.initials: LA
authors.lastname: Sutton
authors.affiliation: Hematology Department and HCT Unit G. Papanicolaou Hospital; Thessaloniki, Greece; Institute of Applied Biosciences; CERTH; Thessaloniki, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
authors.affiliation: Department of Medical and Clinical Genetics; Department of Biomedicine; The Sahlgrenska Academy; Gothenburg University; Gothenburg, Sweden.
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Kanduri
authors.affiliation: Department of Immunology, Genetics and Pathology; Uppsala University; Uppsala, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
mesh_terms: D002843:Chromatin / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005801:Genes, Homeobox; D006657:Histones / Q000235:genetics / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics; D020522:Lymphoma, Mantle-Cell / Q000235:genetics*; D008745:Methylation; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000502:physiology
chemical_list: D002843:Chromatin; D006657:Histones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: DNA methylation; EZH2; HOX genes; chronic lymphocytic leukemia; histone methylation; mantle cell lymphoma